Structure‐activity Relations of Excitatory Amino Acids on Frog and Rat Spinal Neurones

Abstract

I A series of compounds structurally related to glutamic acid has been tested on frog and rat spinal neurones. The substances were added to procaine-containing medium bathing the isolated hemisected spinal cord of the frog, and their potencies in depolarizing motoneurones were assessed by the magnitude of the potential produced in the ventral root. The electrophoretic technique was used to administer the substances around single interneurones of the rat spinal cord and the relative potencies of the compounds as excitants assessed by the magnitude of the currents required to produce similar rates of neuronal firing. 2 Parallel structure-activity relations were observed in the two series of experiments, suggesting that the receptors for excitatory amino acids on frog and rat spinal neurones are similar. 3 Quisqualate, domoate and kainate were the strongest excitants in both animals, with potencies around two orders of magnitude higher than that of L-glutamate. 4 2,4,5-Trihydroxyphenylalanine (6-OH-DOPA) was a stronger excitant and L-3,4-dihydroxyphenylalanine (L-DOPA) a weaker excitant than L-glutamate on frog spinal motoneurones. The former compound was also a more potent convulsant than L-glutamate on intraventricular injection into mouse brain. The lack of activity of 6-OH-DOPA on electrophoretic administration was attributed to oxidation. SUnlike the majority of amino acid excitants, several of the compounds shown in the present work to have moderate excitatory activity are not anionic at physiological pH. This indicates either that two negatively charged groups are not essential for interaction with a common excitatory receptor, or that more than one type of receptor is involved in the actions demonstrated.

Cellular uptake disguises action of L‐glutamate on N‐methyl‐D‐aspartate receptors: With an appendix: Diffusion of transported amino acids into brain slices

“…The NMDA receptor antagonist, DL-2-amino-5-phosphonovalerate (APV) was tested over a range of concentrations against reponses to L-Glu, L-Asp, NMDA and KA in close to maximally-effective concentrations. In slices, the response to NMDA was antagonized more effectively than that to L-Asp; responses to L-Glu and KA were least affected, being less than 40% reduced even at a high ( numerous previous results from iontophoretic experiments on spinal and supraspinal neurones (see Watkins & Evans, 1981;McLennan, 1983;Peet et al, 1983) and from electrophysiological and biochemical experiments in which the compounds have been applied via the bathing medium to isolated preparations of spinal cord (Curtis et al, 1961;Biscoe et al, 1976;Davies et al, 1982) and brain (Constanti et al, 1980;Teichberg et al, 1981;Baudry et al, 1983;Fagni et al, 1983). The one notable difference in the present experiments was the failure of QA to produce significant responses (as also found with the isolated cells) but this appears to be a peculiarity of the immature tissue since QA (3 to 100 tM) induces substantial accumulations of cyclic GMP in slices of adult cerebellum (unpublished results).…”

The primary afferent depolarizing action of kainate in the rat

“…Comparison of a series of excitants showed a more selective structure-activity relationship than that reported for spinal neurones (Biscoe et al, 1976). Relative potencies for those compounds with potencies greater than 0.01 (relative to kainate = 1) are presented in Table 1.…”

Acute hypertension after the local injection of kainic acid into the nucleus tractus solitarii of rats.

“…KA is known to excite most neurons in the CNS in low doses (Shinozaki and Konishi, 1970), to produce depolarization blockade in higher doses (Shinozaki and Konishi, 1970;Biscoe et al, 1976;Pole and Haefely, 1977), and in still higher doses to be neurotoxic. It destroys cell bodies but often preserves nerve fibers when locally injected into the striatum (Schwarcz and Coyle, 1977a), the hippocampus (Nadler et al, 1978;Nadler et al, 1980), or the cerebellum (Herndon and Coyle, 1977).…”